Signal transduction is basic to understanding synaptic plasticity, particularly changes in a neuron's activities resulting from prior stimulation or training. These changes are thought to underlie normal behavioral modifications, such as learning. In addition alterations in these molecular processes, produced by genetic abnormalities, unfavorable environment or as a result of disease or substance abuse, are fundamental to the pathophysiology of mental disorders. Identified sensory neurons mediate defensive reflexes that can be sensitized in the marine mollusk, Aplysia. To be studied are the molecular properties of protein kinase C (PKC) that are pertinent to the presynaptic facilitation underlying this behavioral modification, an elementary form of learning. In this simple nervous system it has been useful to take a reductionist approach reducing behavior to the properties of neuronal molecular constituents. Although there is abundant evidence that cAMP-dependent protein phosphorylation is implicated in both the short- and the long-term forms of sensitization, it recently has become clear that PKC also plays a critical role in the facilitation by strengthening sensory cell synapses. Eight isoforms of PKC have been described, and there is evidence for more than 3 in Aplysia sensory neurons. Each isoform has somewhat different biochemical characteristics. The aim of this project is to relate these special biochemical characteristics to specific physiological mechanisms of synaptic plasticity. To this end, the PKC isoform(s) directly involved in inducing and maintaining presynaptic facilitation will be identified. The molecular properties of all secondary effector enzymes (multifunctional protein kinases) in second-messenger cascades are altered as a consequence of sensitizing stimuli: these alterations result in persistently active kinase activity. Therefore the mechanism(s) by which PKC becomes persistently active will be determined in sensory neurons after long-term sensitizing treatments. There is some indication that, once PKC is activated by stimuli that produce enduring behavioral sensitization, a feed-forward loop is initiated. This loop involves the activation of phospholipase A2 to release arachidonic acid from membrane phospholipids. An isoform of the kinase, a homolog of PKCgamma which is responsive to arachidonic acid as a lipid modulator, might be the persistent kinase activity, and a membrane-associated protein (lipotonin), which, when phosphorylated by PKC, stimulates the activity of the lipase, would be the principal molecular constituents in this regenerative PKC cycle.